Dazoxiben, a thromboxane synthetase inhibitor, in the treatment of Raynaud's syndrome: a double‐blind trial.

Belch, J. J. F.; Cormie, JL; Newman, Peter; McLaren, M.; Barbenel, J.C.; Capell, Hilary A.; Leiberman, P; Forbes, C.D.; Prentice, C. R. M.

doi:10.1111/j.1365-2125.1983.tb02119.x

Cited by 37 publications

(6 citation statements)

References 9 publications

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“…Nevertheless, 12 weeks' treatment with dazoxiben did not produce significant changes in finger-skin temperature, capillary blood cell velocity or in the duration or severity of attacks of Raynaud's phenomenon. These findings are similar to those reported from a 6-week study of patients with Raynaud's phenomenon taking dazoxiben in which there was no significant increase in hand temperature [8]. However, in their study there was an apparent reduction in frequency of Raynaud's attacks.…”

Section: Discussionsupporting

confidence: 89%

Effect of dazoxiben, a thromboxane synthetase inhibitor on skin‐blood flow following cold challenge in patients with Raynaud's phenomenon

Tindall

Tooke

Menys

et al. 1985

Eur J Clin Investigation

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The effects of dazoxiben on finger-blood flow in response to cold challenge were studied in normal subjects and patients with Raynaud's phenomenon. In normal subjects concentrations of TXB2 and 6-oxo-PGF1 alpha were measured in blood taken from dorsal hand veins following cold challenge. In a parallel multicentre study we examined the effects of dazoxiben on finger temperature and capillary blood cell velocity in patients with Raynaud's phenomenon. Dazoxiben did not affect finger arterial inflow at rest or during cold challenge in patients or controls. However in both groups, recovery was quicker after cold challenge on dazoxiben treatment. In patients median flow was 5 ml (100(-1) ml) min-1 (range 1-10) v. 2 (0.5-15), P less than 0.05 dazoxiben v. placebo at 15 min after cold challenge. However, in normal subjects this did not prove to be statistically significant. In normal subjects there was a fall in TXB2 concentrations and relative rise in 6-oxo-PGF1 alpha following dazoxiben treatment indicating redirection of prostaglandin endoperoxides towards synthesis of PGI2. Comparison of the sum-total output of each eicosanoid following treatment with dazoxiben revealed a 65% reduction in TXB2 concentrations (P less than 0.025 compared with placebo) and a 40% increase in 6-oxo-PGF1 alpha concentrations (P less than 0.05 compared with placebo). However a simultaneous increase in concentrations of FPA indicated generation of thrombin, probably at the needle tip. Long-term treatment with dazoxiben resulted in no significant change in finger-skin temperature or capillary blood cell velocity, duration, or severity of attacks of Raynaud's phenomenon.

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Section: Discussionsupporting

confidence: 89%

Effect of dazoxiben, a thromboxane synthetase inhibitor on skin‐blood flow following cold challenge in patients with Raynaud's phenomenon

Tindall

Tooke

Menys

et al. 1985

Eur J Clin Investigation

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“…In a number of these diseases, the balance between TxA 2 and prostacyclin is altered, leading to excessive vasoconstriction and hemostatic disorders. Indeed, in patients with primary vascular diseases involving excessive vasoconstriction, such as migraine headache (43), primary pulmonary HT (22), and Raynaud's disease (68), TxA 2 production is elevated, and the TxS inhibitors CGS-13080 and dazoxiben have been used successfully in the treatment of the latter two diseases (7,66). Findings from animal studies support the proposed relationship between TxA 2 and the development of these diseases (14,26).…”

Section: The Role Of Txa 2 In CV Homeostasis: Historical Viewpointmentioning

confidence: 74%

Sympathy for the devil: the role of thromboxane in the regulation of vascular tone and blood pressure

Sellers

Stallone²

2008

American Journal of Physiology-Heart and Circulatory Physiology

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Historically, the vasodilatory prostanoids, especially prostacyclin and prostaglandin E(2), are believed to contribute significantly to the regulation of normal vascular tone and blood pressure (BP), primarily by counteracting the prevailing effects of the systemic vasoconstrictor systems, including angiotensin II, the catecholamines, and vasopressin. In contrast, the primary vasoconstrictor prostanoid thromboxane A(2) (TxA(2)) is produced in far smaller quantities in the normal state. While TxA(2) is believed to play a significant role in a variety of cardiovascular diseases, such as myocardial infarction, cerebral vasospasm, hypertension, preeclampsia, and various thrombotic disorders, its role in the regulation of vascular tone and BP in the normal physiological state is, at best, uncertain. Numerous studies have firmly established the dogma that TxA(2), while important in pathophysiological states in males, plays little or no role in the regulation of vascular tone or BP in females, except in the pulmonary vasculature. However, this concept is largely based on the predominant and preferential use of males in animal and human studies. Recent studies from our laboratory and others challenge this dogma and reveal that the TxA(2) pathway in the systemic vascular wall is an estrogen-dependent mechanism that appears to play an important role in the regulation of vascular tone and BP in females, in both normal and pathophysiological states. It is proposed that the potent vasoconstrictor action of TxA(2) is beneficial in the female in the normal state by acting as a local counterregulatory mechanism to increase vascular tone and BP and defend against hypotension that could result from the multiple estrogen-sensitive local vasodilator mechanisms present in the female vascular wall. Validation of this proposal must await further studies at the systemic, tissue, and molecular levels.

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“…Animal studies have also revealed a similar relationship between TxA 2 and excessive pulmonary vasoconstriction (11,22). Furthermore, TxS inhibitors such as CGS-13080 and Daz have been used successfully in the treatment of PPH and Raynaud's Disease (7,65).…”

Section: Clinical Significance Of the Present Findingsmentioning

confidence: 96%

Estrogen potentiates constrictor prostanoid function in female rat aorta by upregulation of cyclooxygenase-2 and thromboxane pathway expression

Li¹,

Li²,

Stallone³

2008

American Journal of Physiology-Heart and Circulatory Physiology

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Estrogen potentiates vascular reactivity to vasopressin (VP) by enhancing constrictor prostanoid function. To determine the cellular and molecular mechanisms, the effects of estrogen on arachidonic acid metabolism and on the expression of constrictor prostanoid pathway enzymes and endoperoxide/thromboxane receptor (TP) were determined in the female rat aorta. The release of thromboxane A2 (TxA2) and prostacyclin (PGI2) was measured in male (M), intact-female (Int-F), ovariectomized-female (OvX-F), and OvX + 17beta-estradiol-replaced female (OvX + ER-F) rats. The expression of mRNA for cyclooxygenase (COX)-1, COX-2, thromboxane synthase (TxS), and TP by aortic endothelium (Endo) and vascular smooth muscle (VSM) of these four experimental groups was measured by RT-PCR. The expression of COX-1, COX-2, and TxS proteins by Endo and VSM was also estimated by immunohistochemistry (IHC). Basal release of TxA2 and PGI2 was similar in M (18.8 +/- 1.9 and 1,723 +/- 153 pg/mg ring wt/45 min, respectively) and Int-F (20.2 +/- 4.2 and 1,488 +/- 123 pg, respectively) rat aortas. VP stimulated the dose-dependent release of TxA2 and PGI2 from both male and female rat aorta. OvX markedly attenuated and ER therapy restored VP-stimulated release of TxA2 and PGI2 in female rats. No differences in COX-1 mRNA levels were detected in either Endo or VSM of the four experimental groups (P > 0.1). The expression of both COX-2 and TxS mRNA were significantly higher (P < 0.05) in both Endo and VSM of Int-F and OvX + ER-F, compared with M or OvX-F. Expression of TP mRNA was significantly higher in VSM of Int-F and OvX + ER-F compared with M or OvX-F. IHC revealed the uniform staining of COX-1 in VSM of the four experimental groups, whereas staining of COX-2 and TxS was greater in Endo and VSM of Int-F and OvX + ER-F than in OvX-F or M rats. These data reveal that estrogen enhances constrictor prostanoid function in female rat aorta by upregulating the expression of COX-2 and TxS in both Endo and VSM and by upregulating the expression of TP in VSM.

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Dazoxiben, a thromboxane synthetase inhibitor, in the treatment of Raynaud's syndrome: a double‐blind trial.

Cited by 37 publications

References 9 publications

Effect of dazoxiben, a thromboxane synthetase inhibitor on skin‐blood flow following cold challenge in patients with Raynaud's phenomenon

Effect of dazoxiben, a thromboxane synthetase inhibitor on skin‐blood flow following cold challenge in patients with Raynaud's phenomenon

Sympathy for the devil: the role of thromboxane in the regulation of vascular tone and blood pressure

Estrogen potentiates constrictor prostanoid function in female rat aorta by upregulation of cyclooxygenase-2 and thromboxane pathway expression

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